3-Oxa prostaglandin F{331 -type compounds

ABSTRACT

This invention is a group of 3- and 4-Oxa-PG-type compounds, and processes for making them. These compounds are useful for a variety of pharmacological purposes, including anti-ulcer, inhibition of platelet aggregation, increase of nasal patency, labor inducement at term, and wound healing.

United States Patent 1 1 1 1] 3,923,861

Nelson 1 Dec. 2, 1975 3-OXA PROSTAGLANDIN FB-TYPE 260/468 G; 260/468 K;260/484 R; 260/488 COMPOUNDS Inventor: Norman A. Nelson, Galesburg,

Mich.

Assignee: The Upjohn Company, Kalamazoo,

Mich.

Filed: Apr. 17, 1974 Appl. No.: 46 1,508

Related U.S. Application Data Continuation of Ser. No. 332,067, Feb. 13,1973, abandoned, which is a continuation-in-part of Ser. No. 47,169,June 17, 1970, abandoned.

Foreign Application Priority Data July 29, 1969 United Kingdom 38073/69U.S. Cl...... 260/468 D; 260/211 R; 260/240 R; 260/247.2 R; 260/268 R;260/243.6 S; 260/326.2; 260/340.4; Zoo/345.8; 260/345.4;260/347.4;260/410 R; 260/429.4; 260/439 R; 260/448 R; 260/448.8 R;260/456 R;

R; 260/50l.l; 260/501.15; 260/50l.l7; 260/5OL2; 260/514 D; 260/533 H;260/615 Int. Cl. C07C 61/38; C07C 69/74 Field of Search 260/468 D, 514 D[56] References Cited FOREIGN PATENTS OR APPLICATIONS 2,036,471 2/1971Germany 260/468 Primary Examiner-Robert Gerstl Attorney, Agent, orFirm-Morris L. Nielsen 57 ABSTRACT 70 Claims, No Drawings 1 3-0XAPROSTAGLANDIN F, -TYPE COMPOUNDS cRoss REFERENCE TO RELATED APPLICATIONSThis application is a continuation of my copending application Ser. No.332,067, filed Feb. 13, 1973, now abandoned, which was acontinuation-in-part of my then copending application Ser. No. 47,169,filed June 17, 1970, now abandoned.

BACKGROUND OF THE INVENTION This invention relates to compositions ofmatter, andand to novel chemical intermediates useful in those novelmethods.

Each of the above-mentioned known prostaglandins is a derivative ofprostanoic acid which has the following structure and atom numbering:

C H I WAY/1 W A systematic name for prostanoic acid is 7-[(2B-octyl)-cyclopentl a-yl ]heptanoic acid.

PGE, has the following structure:

PGF has the following structure:

PGB, has the following structure:

COOH

Each of the known prostaglandins PGE PGF PGF PGA and PGB, has astructure the same as that shown for the corresponding PG, compoundexcept that in each, C-5 and G6 are linked with a cis carbon-carbondouble bond. For example, PGE has the following structure:

/ W COOH H0 H OH Each of the known P6 prostaglandins has a structure thesame as that of the PG, compounds except that in each, C-17 and C-18 arelinked with a cis carboncarbon double bond. For example, PGE,, has thefollowing structure:

"\ZA/W H Vlll Each dihydro derivative of PGE,, PGE,,, PGF, PGA,, andPGB, has a structure the same as that shown for the corresponding PG,compound except that in each, C-1 3 and C-14 are linked with acarbon-carbon single bond. For example, dihydro-PGB, has the followingstructure:

The prostaglandin formulas mentioned above each have several centers ofasymmetry. As drawn, formulas II to IX each represents the particularoptically active form of the prostaglandin obtained from certainmammalian tissues, for example, sheet vesicular glands, swine lung, andhuman seminal plasma, or by reduction or dehydration of a prostaglandinso obtained. See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1(1968 and references cited therein. The mirror image of each formularepresents a molecule of the enantiomer of that prostaglandin. Theracemic form of the prostaglandin consists of equal numbers of two typesof molecules, one represented by one of the above formulas and the otherrepresented by the mirror image of that formula. Thus, both formulas areneeded to define a racemic prostaglandin. See Nature 212, 38 (1966) fordiscussion of the stereochemistry of the prostaglandins.

In formulas l-IX, as well as in the formulas given hereinafter, brokenline attachments to the cyclopentane ring indicate substituents in alphaconfiguration, i.e., below the plane of the cyclopentane ring. Heavysolid line attachments to the cyclopentane ring indicate substituents inbeta configuratiom'ie, above the plane of the cyclopentane ring.

Prostaglandins with carboxyl-terminated side chains attached to thecyclopentane ring in beta configuration are also known. These arederivatives of 8-iso-prostanoic acid which has the following formula:

A systematic name for 8-iso-prostanoic acid is 7- [(2B-octyl)-cyclopentl B-yl]heptanoic acid.

The side-chain hydroxy at C-l in formulas II to IX is in alpha (S)configuration. See Nature 212, 38 (1966) for discussion of thestereochemistry of the prostaglandins.

PGE,, PGE dihydro-PGE and the corresponding PGFa PGF PGA, and PGBcompounds, and their esters, acylates, and pharmacologically acceptablesalts, are extremely potent in causing various biological responses. Forthat reason, these compounds are useful for pharmacological purposes.See, for example, Bergstrom et al., Pharmacol. Rev. 20, l (1968), andreferences cited therein. A few of those biological responses aresystemic blood pressure lowering in the case of the PGE and PGAcompounds as measured, for example, in anesthetized (pentobarbitalsodium) pentoliniumtreated rats with indwelling aortic and right heartcannulas; stimulation of smooth muscle as shown, for example, by testson strips of guinea pig ileum, rabbit duodenum, or gerbil colon;potentiation of other smooth muscle stimulants; antilipolytic activityas shown by antagonism of epinephrine-induced mobilization of free fattyacids or inhibition of the spontaneous release of glycerol from isolatedrat fat pads; inhibition of gastric secretion in the case of the PGE andPGA compounds as shown in dogs with secretion stimulated by food orhistamine infusion; activity on the central nervous system; controllingspasm and facilitating breathing in asthmatic conditions; decreasingblood platelet adhesiveness as shown by platelet-to-glass adhesiveness,and inhibition of blood platelet aggregation and thrombus formationinduced by various physical stimuli, e.g., arterial injury, and variousbiochemical stimuli, e.g., ADP, ATP, serotonin, thrombin, and collagen;and in the case of the PGE and PGB compounds, stimulation of epidermalproliferation and keratinization as shown when applied in culture toembryonic chick and rat skin segments.

Because of these biological responses, these known prostaglandins areuseful to study, prevent, control, or alleviate a wide variety ofdiseases and undesirable physiological conditions in birds and mammals,includ ing humans, useful domestic animals, pets, and zoologicalspecimens, and in laboratory animals, for example, mice, rats, rabbits,and monkeys.

For example, these compounds, and especially the PGE compounds, areuseful in mammals, including man, as nasal decongestants. For thispurpose, the compounds are used in a dose range of about 10 lg. to about10 mg. per ml. of a pharmacologically suitable 4 liquid vehicle or as anaerosol spray, both for topical application.

The PGE, PGF PGF and PGA compounds are useful in the treatment ofasthma. For example, these compounds are useful as bronchodilators or asinhibitors of mediators, such as SRS-A, and histamine which are releasedfrom cells activated by an antigen-antibody complex. Thus, thesecompounds control spasm and facilitate breathing in conditions such asbronchial asthma, bronchitis, bronchiectasis, pneumonia and emphysema.For these purposes, these compounds are administered in a variety ofdosage forms, e.g., orally in the form of tablets, capsules, or liquids;rectally in the form of suppositories; parenterally, subcutaneously, orintramuscularly, with intravenous administration being preferred inemergency situations; by inhalation in the form of aerosols or solutionsfor nebulizers; or by insufflation in the form of powder. Doses in therange of about 0.01 to 5 mg. per kg. of body weight are used 1 to 4times a day, the exact dose depending on the age, weight, and conditionof the patient and on the frequency and route of administration. For theabove use these prostaglandins can be combined advantageously with otheranti-asthmatic agents, such as sympathomimetics (isoproterenol,phenylephrine, ephedrine, etc.); xanthine derivatives (theophylline andaminophylline); and cortico-steroids (ACTH and predinisolone). Regardinguse of these compounds see South African Pat. No. 681,055.

The PGE and PGA compounds are useful in mammals, including man andcertain useful animals, e.g., dogs and pigs, to reduce and controlexcessive gastric secretion, thereby reducing or avoidinggastrointestinal ulcer formation, and accelerating the healing of suchulcers already present in the gastrointestinal tract. For this purpose,the compounds are injected or infused intravenously, subcutaneously, orintramuscularly in an infusion close range about 0.1 ug. to about 500[.Lg. per kg. of body weight per minute, or in a total daily dose byinjection or infusion in the range about 0.1 to about 20 mg. per kg. ofbody weight per day, the exact dose depending on the age, weight, andcondition of the patient or animal, and on the frequency and route ofadministration.

The PGE, PGF and PGFp compounds are useful whenever it is desired toinhibit platelet aggregation, to reduce the adhesive character ofplatelets, and to remove or prevent the formation of thrombi in mammals,including man, rabbits, and rats. For example, these compounds areuseful in the treatment and prevention of myocardial infarcts, to treatand prevent post-operative thrombosis, to promote patency of vasculargrafts following surgery, and to treat conditions such asatherosclerosis, arteriosclerosis, blood clotting defects due tolipemia, and other clinical conditions in which the underlying etiologyis associated with lipid imbalance or hyperlipidemia. For thesepurposes, these compounds are administered systemically, e.g.,intravenously, subcutaneously, intramuscularly, and in the form ofsterile implants for prolonged action. For rapid response, especially inemergency situations, the intrablood substitutes, and other fluids whichare used in artificial extracorporeal circulation and perfusion ofisolated body portions, e.g., limbs and organs, whether attached to theoriginal body, detached and being preserved or prepared for transplant,or attached to a new body. During these circulations and perfusions,aggregated platelets tend to block the blood vessels and portions of thecirculation apparatus. This blocking is avoided by the presence of thesecompounds. For this purpose, the compound is added gradually or insingle or multiple portions to the circulating blood, to the blood ofthe donor animal, to the perfused body portion, attached or detached, tothe recipient, or to two or all of those at a total steady state dose ofabout 0.001 to mg. per liter of circulating fluid. It is especiallyuseful to use these compounds in laboratory animals, e.g., cats, dogs,rabbits, monkeys, and rats, for these purposes in order to develop newmethods and techniques for organ and limb transplants.

PGE compounds are extremely potent in causing stimulation of smoothmuscle, and are also highly active in potentiating other known smoothmuscle stimulators, for example, oxytocic agents, e.g., oxytocin, andthe various ergot alkaloids including derivatives and analogs thereof.Therefore, PGE for example, is useful in place of or in combination withless than usual amounts of these known smooth muscle stimulators, forexample, to relieve the symptoms of paralytic ileus, or to control orprevent atonic uterine bleeding after abortion or delivery, to aid inexpulsion of the placenta, and during the puerperium. For the latterpurpose, the PGE compound is administered by intravenous infusionimmediately after abortion or delivery at a dose in the range about 0.01to about 50 pg. per kg. of body weight per minute until the desiredeffect is obtained. Subsequent doses are given by intravenous,subcutaneous, or intramuscular injection or infusion during puerperiumin the range 0.01 to 2 mg. per kg. of body weight per day, the exactdose depending on the age, weight, and condition of the patient oranimal.

The PGE and PGA compounds are useful as hypotensive agents to reduceblood pressure in mammals, including man. For this purpose, thecompounds are administered by intravenous infusion at the rate about0.01 to about 50 pg. per kg. of body weight per minute or in single ormultiple doses of about to 500 pg. per kg. of body weight total per-day.

The PGE, PGF and PGF compounds are useful in place of oxytocin to inducelabor in pregnant female animals, including man, cows, sheep, and pigs,at or near term, or in pregnant animals with intrauterine death of thefetus from about 20 weeks to term. For this purpose, the compound isinfused intravenously at a dose of 0.01 to 50 pg per kg. of body weightper minute until or near the termination of the second stage of labor,i.e., expulsion of the fetus. These compounds are especially useful whenthe female is one or more weeks post-mature and natural labor has notstarted, or 12 to 60 hours after the membranes have ruptured and naturallabor has not yet started. An alternative route of administration isoral.

The PGE, PGF and PGF compounds are useful for'controlling thereproductive cycle in ovulating female mammals, including humans andanimals such as monkeys, rats, rabbits, dogs, cattle, and the like. Bythe term ovulating female mammals is meant animals which are matureenough to ovulate but not so old that regular ovulation has ceased. Forthat purpose PGF for example, is administered systemically at a doselevel in the range 0.01 mg. to about 20 mg. per kg. of body weight ofthe female mammal, advantageously during a span of time startingapproximately at the time of ovulation and ending approximately at thetime of menses or just prior to menses. Intravaginal and intrauterineare alternative routes of administration. Additionally, expulsion of anembryo or a fetus is accomplished by similar administration of thecompound during the first third of the normal mammalian gestationperiod.

The PGE and PGF compounds are useful in causing cervical dilation inpregnant and nonpregnant female mammals for purposes of gynecology andobstetrics. In labor induction and in clinical abortion produced bythese compounds, cervical dilation is also observed. In cases ofinfertility, cervical dilation produced by PGE and PCP compounds isuseful in assisting sperm movement to the uterus. Cervical dilation byprostaglandins is also useful in operative gynecology such as D and C(Cervical Dilation and Uterine Curettage) where mechanical dilation maycause perforation of the uterus, cervical tears, or infections. It isalso useful in diagnosti'c procedures where dilation is necessary fortissue examination. For these purposes, the PGE and PCP compounds areadministered locally or systemically. PGE for example, is administeredorally or vaginally at doses of about 5 to 50 mg. per treatment of anadult female human, with from one to five treatments per 24 hour period.PGE is also administered intramuscularly or subcutaneously at doses ofabout one to 25 mg. per treatment. The exact dosages for these purposesdepend on the age, weight, and condition of the patient or animal.

As mentioned above, the PGE compounds are potent antagonists ofepinephrine-induced mobilization of free fatty acids. For this reason,this compound is useful in experimental medicine for both in vitro andin vivo studies in mammals, including man, rabbits, and rats, intendedto lead to the understanding, prevention, symptom alleviation, and cureof diseases involving abnormal lipid mobilization and high free fattyacid levels, e. g., diabetes mellitus, vascular diseases, andhyperthyroidism.

The PGA compounds and derivatives and salts thereof increase the flow ofblood in the mammalian kidney, thereby increasing volume and electrolytecontent of the urine. For that reason, PGA compounds are useful inmanaging cases of renal disfunction, especiallythose involving blockageof the renal vascular bed. lllustratively, the PGA compounds are usefulto alleviate and correct cases of edema resulting, for example, frommassive surface burns, and in the management of shock. For thesepurposes, the PGA compounds are preferably first administered byintravenous injection at a dose in the range of 10 to 1000 pg. per kg.of body weight or by intravenous infusion at a dose in the range 0.1 to20 pg. per kg. of body weight per minute until the desired effect isobtained. Subsequent doses are given by intravenous, intramuscular, orsubcutaneous injection or infusion in the range 0.05 to 2 mg. per kg. ofbody weight per day.

The PGE and PGE compounds promote and accelerate the growth of epidermalcells and keratin in animals, including humans, useful domestic animals,pets, zoological specimens, and laboratory animals. For that reason,these compounds are useful to promote and accelerate healing of skinwhich has been damaged, for

example, by burns, wounds, and abrasions, and after surgery. Thesecompounds are also useful to promote and accelerate adherence and growthof skin autografts, especially small, deep (Davis) grafts which areintended to cover skinless areas by subsequent outward growth ratherthan initially, and to retard rejection of homografts.

For these purposes, these compounds are preferably administeredtopically at or near the cite where cell growth and keratin formation isdesired, advantageously as an aerosol liquid or micronized powder spray,as an isotonic aqueous solution in the case of wet dressings, or as alotion, cream, or ointment in combination with the usualpharmaceutically acceptable diluents. In some instances, for example,when there is substantial fluid loss as in the case of extensive burnsor skin loss due to other causes, systemic administration isadvantageous, for example, by intravenous injection or infusion,separate or in combination with the usual infusions of blood, plasma, orsubstitutes thereof. Alternative routes of administration aresubcutaneous or intramuscular near the site, oral, sublingual, buccal,rectal, or vagina]. The exact dose depends on such factors as the routeof administration, and the age, weight, and condition of the subject. Toillustrate, a wet dressing for topical application to second and/orthird degree burns of skin area to square centimeters wouldadvantageously involve use of an isotonic aqueous solution containing 1to 500 pug/ml. of the PGB compound or several times that concentrationof the PGE compound. Especially for topical use, these prostaglandinsare useful in combination with antibiotics, for example, gentamycin,neomycin, polymyxic B, bacitracin, spectinomycin, and oxytetracycline,with other antibacterials, for example, mafenide hydrochloride,sulfadiazine, furazolium chloride, and nitrofurazone, and with corticoidsteroids, for example, hydrocortisone, prednisolone, methylprednisolone,and fluprednisolone, each of those being used in the combination at theusual concentration suitable for its use alone.

SUMMARY OF THE INVENTION The novel compound, 4-oxa-PGE is represented bythe formula:

Xll

8 Some of the novel prostaglandin analogs of this invention have asmaller or greater number of carbon atoms than the formulas shown above,in either the carboxy-terminated side chain or the alkyl-terminated sidechain.

For example, five of the novel prostaglandin analogs of this inventionare represented by the formulas:

C0OH X'H HQ H OH XIV c cEc-CH -O-CH C XVI H UH XVII

better be understood by reference to the structure and numbering systemof prostanoic acid (Formula I, above). That formula has seven carbonatoms in the carboxy-terminated chain and eight carbon atoms in thehydroxy-containing chain. In these names, 3-oxa and 4-oxa indicate anoxa oxygen (-O) in place of the 3-methylene and 4-methylene,respectively of 9 the PG compound.

The use of .nor or dinor in the names for the novel compounds of thisinvention indicates the absence of one or two of the chain carbon atomsand the attached hydrogen atoms. The number or numbers in front of nor,or dinor indicate which of the original prostanoic acid carbon atoms aremissing in the named compound.

The use of homo or dihomo as in the names of the formula-XIV and -XVIIexamples indicate one or two additional carbon atoms in thecarboxy-terminated side chain. In the name of the formula-XIV example4a,4b-dihomo indicates two additional carbon atoms specifically betweenthe oxygen atom at 4 and the C-5 carbon atom. There are, therefore,eight carbon atoms and one oxygen atom in that side chain instead of thesix carbon atoms and one oxygen atom of the normal 3-oxa structure ofthis invention.

In the name of the formula XVI example, 20- methyl indicates that amethyl group replaces a hydrogen on C20. The methyl-terminated chain ofthat example therefore has nine carbon atoms.

Where there is branching or fluoro substitution in the side chains, thepoints of attachment to the side chains are indicated in theconventional manner, following the atomic numbering of the prostanoicacid skeleton (I).

Novel compounds of this invention with epi configuration for the hydroxyat 015 are so designated by using IS-beta in the name. An example is thename given above for the compound of formula XIV. If beta does notappear in the name, the natural configuration for the C-l5 hydroxy,identified as the S configuration for PGE is to be assumed.

The following formulas represent the novel 3-oxa and 4-oxa compounds ofthis invention in the same optically active fonn as the naturallyoccuring prostaglandins.

-continued w w R w W o R H C C Ri k Jo ha w c R 4 x O R H/ C m H m Q mcHo 4 C H CH0 H H H "a C c C c U H O\ O 0 5 0 5 3 3 4 4 M M m x x x m Rg o 6 R H O R R w .1 4 4 C R JC R C s s R G R RlJTm "M H 0 4 a H C 0 H C0 H c C C H F C m w L R o 0 C s a R H Q H H 2 H m a H nWHQ H 41 5 5 5 6L U R m m C O 1 a c 5 a 5 e IJCIR R JT R ,0 w a c. 4 2 H .2 H a C m c CH H Formulas XVIII to XXVII represent 3-oxa and 4-oxa compounds of thePGE type. Formulas XXVIII to 60 XXXVII represent 3-oxa and 4-oxacompounds of the PGF type. Formulas XXXVIII to XLVII represent 3-oxa and4-oxa compounds of the PGA type. Formulas XLVIII to LVII represent 3-oxaand 4-oxa compounds of the PGB type.

In formulas XVIII to R is hydrogen, alkyl of one to 12 carbon atoms,inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one to 3chloro or alkyl of one to 4 carbon atoms, inclusive, or ethylsubstituted in the B-position with 3 chloro, 2 or 3 bromo, or 1, 2, or 3iodo. R is alkyl of one to 10 carbon atoms, inclusive, substituted withzero to 3 fluoro. Q is wherein R is hydrogen or alkyl of one to 4 carbonatoms, inclusive. R is alkyl of one to 4 carbon atoms, inclusive,substituted with zero, one, 2 or 3 fluoro. R R R and R are hydrogen oralkyl of one to 4 carbon atoms, inclusive. The divalent moiety C,,I-Irepresents alkylene of one to 10 carbon atoms, inclusive, with one to 5carbon atoms, inclusive, between -CI-I and O-. The divalent moietyC,,,I-I represents alkylene of one to 9 carbon atoms, inclusive, withone to 4 carbon atoms, inclusive, between -CI-I and -O. The divalentmoiety C,,H represents alkylene of one to 8 carbon atoms, inclusive,with one, 2, or 3 carbon atoms between Cl-I=CII or --C E C- and O-'. Thedivalent moiety C I-I- represents alkylene of one to 7 carbon atoms,inclusive, with one or 2 carbon atoms between Cl-I=)\ CH or ---C C-- and--O-. The divalent moiety C I-I represents alkylene of one to 4 carbonatoms, inclusive. The wavy line indicates attachment of the hydroxylgroup to the ring in alpha or beta configuration.

Formulas XVIII through LVII include the separate isomes wherein Q iseither i.e. where the hydroxyl is in either alpha natural) or betaconfiguration. Referring to the prostanoic acid atom numbering (formulaI above), the point of attachment corresponds to C-l5, and, herein,regardless of the variation in the G1 to C-7 carboxy chain, theseepimers are referred to as C- epimers.

Formulas XXVIII through XXXVII wherein the C-9 hydroxyl (followingprostanoic acid atom numbering) is attached to the cyclopentane with awavy line include both PGF and PGF -type compounds.

Included in formulas XX, XXI, xXX, XXXI, XL, XLI, L, and LI are both thecis and the trans compounds with respect to the O5 to C-6 double bond inthe carboxyl-terminated side chain. In all of the compounds containingthe C -to-C double bond, that double bond is in trans configuration, andthe chain containing that moiety is attached to the cyclopentane ring inbeta configuration in compounds encompassed by formulas XVIII to XLVII.

The novel 3-oxa and 4-oxa compounds of this invention include racemiccompounds and both optically active enantiomeric forms thereof. Asdiscussed hereinabove, two structural formulas are required to defineaccurately these racemic compounds. The formulas as drawn herein areintended to represent compounds with the same configuration as thenaturally-occurring prostaglandins. However, for convenience in thecharts herein only a single structural formulas is used, for example inChart E, to define not only the optically active form but also theracemic compounds which generally undergo the same reactions.

Formula XVIII represents 3-oxa-PGE (formula XI hereinabove) when C I'Iis (CH2)3 Q is H OH,

R R and R are hydrogen, and R is n-pentyl.

With regard to formulas XVIII to LVII, examples of alkyl of one to 4carbon atoms, inclusive, are methyl, ethyl, propyl, butyl, and isomericfo'rms thereof. Examples of alkyl of one to 8 carbon atoms, inclusive,are those given above, and pentyl, hexyl, heptyl, octyl, and isomericforms thereof. Examples of alkyl of one to 12 carbon atoms, inclusive,are those given above, and nonyl, decyl, undecyl, dodecyl, and isomericforms thereof. Examples of cycloalkyl of 3 to 10 carbon atoms,inclusive, which includes alkyl-substituted cycloalkyl, are cyclopropyl,2-methylcyclopropyl, 2,2- dimethylcyclopropyl, 2,3-diethylcyclopropyl,2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl,2,3,4-triethylcyclobutyl, cyclopentyl, 2,2- dimethylcyclopentyl,3-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl,4-tert-butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Examples of aralkylof 7 to 12 carbon atoms, inclusive, are benzyl, phenethyl,l-phenylethyl, 2-phenylpropyl, 4- phenylbutyl, 3-phenylbutyl, 2-(l-naphthylethyl), and l-( Z-naphthylmethyl), Examples of phenylsubstituted by one to 3 chloro or alkyl of one to 4 carbon atoms,inclusive, are p chlorophenyl, m-chlorophenyl, ochlorophenyl,2,4-dichlorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m-tolyl, o-tolyl,p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl,4-chloro-2-methylphenyl, and 2,4-dichloro-3-methylphenyl.

Examples of alkyl of one to 10 carbon atoms, inclusive, substituted withone to 3 tluoro, are fluoromethyl,

2-fluoroethyl, 2-fluorobutyl, 3-fluorobutyl, 4-fluorobutyl,S-fluoropentyl, 4-fluoro-4-methylpentyl, 3- fluoroisoheptyl,8-fluorooctyl, 3,4-difluorobutyl, 4,4- difluoropentyl,5,5-difluoropentyl, 5,5,5-trifluoropentyl, and 10,10,10-trifluorodecyl.

Examples of alkylene within the various scopes of C -H, C H C,,H C I-Iand C I-I as those are defined above, are methylene,ethylene,,trimethylene, tetramethylene, pentamethylene, and thosealkylene with one or more alkyl substituents on one or more carbon atomsthereof, e.g., CH(CH CI-I(CH CI-I -CI-I CI-I(CI-I CI-I(CI-I- )-CI-I(CI-ICI-I --C(CH3)2, -CI-I- CI-I(CI-I )CI-I -CH CH CI-I(CI-I CI-I CH--CI-I(CH )Cl-I(CI-I )CH -CH CH- 2CH2-CH2C(CH3)2CH2 and -CH2CH- -CI-ICI-I CI-I(CH The novel formula XVIII-XXVII PGE-type 3-oxa and 4-oxacompounds, the novel formulas XXVIII-XXXVII PGFa -type and PGF -type3-oxa and 4-oxa compounds, the novel formula XXXVIII-XLVII pGA-type3-oxa and 4-oxa compounds, and the novel formula XLVIII-LVII PGB-type3-oxa and 4-oxa compounds, and their racemic forms, each cause thebiological responses described above for the PGE, PGF PGF PGA, and PGBcompounds, respectively, and eac of these novel compounds is accordinglyuseful for the above-described corresponding purposes, and is used forthose purposes in the same manner as described above.

The known PGE, PGF PGF PGA, and PGE compounds uniformly cause multiplebiological responses even at low doses. For example, PGE and PGE bothcause vasodepression and smooth muscle stimulation at the same time theyexert antilipolytic activity. Moreover, for many applications, theseknown prostaglandins have an inconveniently short duration of biologicalactivity. In striking contrast, the novel formula XVIII-to-LVII analogsand their racemic forms are substantially more specific with regard topotency in causing prostaglandin-like biological responses, and have asubstantially longer duration of biological activity. Therefore, each ofthese novel prostaglandin analogs is useful in place of one of thecorresponding above-mentioned known prostaglandins for at least one ofthe pharmacological purposes indicated above for the latter, and issurprisingly and unexpectedly more useful for that purpose because ithas a different and narrower spectrum of biological activity than theknown prostaglandin, and therefore is more specific in its activity andcauses smaller and fewer undesired side effects than the knownprostaglandin. Moreover, because of its prolonged activity, fewer andsmaller doses of the novel prostaglandin analog can frequently be usedto attain the desired result.

To obtain the optimum combination of biological potency specificity andduration of activity, certain compoun s within the scope of formulasXVIII to LVII are preferred. For example, it is preferred that thecarboxyterminated chain in each formula contain a chain of six atomsbetween the carboxyl and the cyclopentane ring. One of those six atomswill be the oxa atom and the other five will be carbon atoms.Accordingly and with reference to formulas XVIII t'o LVII, it ispreferred that -C,,l-I represent a 3-carbon divalent chain, that -C,,,Hrepresent a 2-carbon divalent chain, and that C,,H represent a divalentcarbon atom. These preferences do not exclude additional carbon atoms(alkyl groups) as branching.

A seven-atom carboxyl terminated chain is not included in the compoundsof formulas XXI, XXIII, XXVII, XXXI, XXXIII, XXXVII, XLI, XLIII, XLVII,LI, LIII, and LVII, i.e., formulas wherein the carboxyterminated sidechain is 4-oxa and contains a carboncarbon double or triple bond. Ineach of those compounds, the q of -C I-I is at least one, and at leastseven atoms, one oxygen (oxa) and six carbons, are present between thecarboxyl and the cyclopentane ring. In these compounds, the preferenceis for that minimum chain, i.e., q is one.

Another preference for the compounds of formulas XVIII to LVII is that RR R R and R be hydrogen or methyl. All of those R groups can behydrogen, all can be methyl, or there can be any of the possiblecombinations of hydrogen and methyl. It is especially preferred forprolonged duration of biological activity that both R and R; be methyl,and/or that R; be methyl.

Certain variations in the nature of R in formulas XVIII-XXV,XXVIII-XXXV, XXXVIIl-XLV, and XLVIIl-LV are especially important. In theknown prostaglandins, e.g., PGE the portion of the moleculecorresponding to R in the above-mentioned formulas is pentyl. It ispreferred that R be pentyl in formulas XVIII-XXV, XXVIII-XXXV,XXVII-XLV, and XLVIII-LV. It is also preferred that R be straight chainalkyl of 3 to 7 carbon atoms, inclusive, with or without afluorosubstituent at the l-position e.g., CI-IF(CI-I CI-I wherein g is one to5. Alternately, R is represented by wherein R is hydrogen or fluoro andg is one, 2, 3, 4, or 5. Pentyl and l-fluoropentyl are, of course,included in this preference.

In compounds of formulas XXVI, XXVII, XXXVI, XXXVII, XLVI, XLVII, LVI,and LVII, it is preferred that C H be methylene and that R be ethyl.

Another advantage of the novel compounds of this invention, especiallythe preferred compounds defined hereinabove, compared with the knownprostaglandins, is that these novel compounds are administeredeffectively orally, sublingually, intravaginally, buccally, or rectally,in addition to usual intravenous, intramuscular, or subcutaneousinjection or infusion methods indicated above for the uses of the knownprostaglandins. These qualities are advantageous because they facilitatemaintaining uniform levels of these compounds in the body with fewer,shorter, or smaller doses, and make possible self-administration by thepatient.

The PGE, PGF PGF PGA, and PGB type 3-oxa and 4-oxa compounds encompassedby formulas XVIII to LVII including the special classes of compoundsdescribed above, are used for the purposes described above in the freeacid form, in ester form, or in pharmacologically acceptable salt form.When the ester form is used the ester is any of those within the abovedefinition of R However, it is preferred that the ester be alkyl of oneto 12 carbon atoms, inclusive. Of those alkyl, methyl and ethyl areespecially preferred for optimum absorption of the compound by the bodyor experimental animal system; and straight-chain octyl, nonyl, decyl,undecyl, and dodecyl are especially preferred for prolonged activity inthe body or experimental animal.

Pharmacologically acceptable salts of these formula XVIII-to-LVIIcompounds useful for the purposes described above are those withpharmacologically acceptable metal cations, ammonium, amine cations, orquaternary ammonium cations.

Especially preferred metal cations are those derived from the alkalimetals, e.g., lithium, sodium and potassium, and from the alkaline earthmetals, e.g., magnesium and calcium, although cationic forms of othermetals, e.g., aluminum, zinc, and iron, are within the scope of thisinvention.

Pharmacologically acceptable amine cations are those derived fromprimary, secondary, or tertiary amines. Examples of suitable amines aremethylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine,triisopropylamine, N-methylhexylamine, decyl- 19 amine, dodecylamine,allylamine, crotylamine, cyclopentylamine, dicyclohexylamine,benzylamine,

dibenzylamine, a-phenylethylamine, ,B-phenylethylamine, ethylenediamine,diethylenetriamine, and like aliphatic, cycloaliphatic, and araliphaticamines containing up to and including about '18 carbon atoms, as well asheterocyclic amines, e.g., piperidine, morpholine, pyrrolidine,piperazine, and lower-alkyl derivatives thereof, e.g.,l-methylpiperidine, 4-ethylmorpholine, l-isopropylpyrrolidine,2-methylpyrrolidine, 1,4- dimethylpiperazine, Z-methylpiperidine, andthe like, as well as amines containing water-solubilizing or hydrophilicgroups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine,N-butylethanolamine, 2-aminol-butanol, 2-amino-2-ethyl-l,3-propanediol,2-amino- 2-methyll-propanol, tris-(hydroxymethyl)aminomethane,N-phenylethanolamine, N-(p-tert-amylphenyl)- diethanolamine,galactamine, N-methylglucamine, N- methylglucosamine, ephedrine,phenylephrine, epinephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammoniumcations are tetramethylammonium, tetraethylammonium,benzyltrimethylammonium, phenyltriethylammonium, and the like.

The 3-oxa and 4-oxa PGE, PGF PGF PGA, and PGE type compounds encompassedby formulas XVIII to LVII including the special classes of compoundsdescribed above, are also used for the purposes described above in freehydroxy form or in the form wherein the hydroxy moieties are transformedto lower alkanoate moieties, e.g., -OH to -OCOCI-l Examples of loweralkanoate moieties are acetoxy, propionyloxy, butyryloxy, valeryloxy,hexanoyloxy, heptanoyloxy, octanoyloxy, and branched chain alkanoyloxyisomers of those moieties. Especially preferred among these alkanoatesfor the above described purposes are the acetoxy compounds. These freehydroxy and alkanoyloxy compounds are used as free acids, as esters, andin salt form all as described above.

As discussed above, the compounds of formulas XVIII to LVII areadministered in various ways for various purposes; e.g., intravenously,intramuscularly, subcutaneously, orally, intravaginally, rectally,buccally, sublingually, topically, and in the form of sterile implantsfor prolonged action. For intravenous injection or infusion, sterileaqueous isotonic solutions are preferred. For that purpose, it ispreferred because of increased water solubility that R in the formulaXVIII- to-LVII compound be hydrogen or a pharmacologically acceptablecation. For subcutaneous or intramuscular injection, sterile solutionsor suspensions of the acid, salt, or ester form in aqueous ornon-aqueous media are used. Tablets, capsules, and liquid preparationssuch as syrups, elixirs, and simple solutions, with the usualpharmaceutical carriers are used for oral sublingual administration. Forrectal or vaginal administration, suppositories prepared as known in theart are used. For tissue implants, a sterile tablet or silicone rubbercapsule or other object containing or impregnated with the substance isused.

The 3-oxa and 4-oxa PGE, PGF PGF PGA, and PGE type compounds encompassedby formulas XVIII to LVII are produced by the reactions and proceduresdescribed and exemplified hereinafter.

The various 3-oxa and 4-oxa PGFO, -type and -type compounds encompassedby formulas XXVllI-XXXVII are prepared by carbonyl reduction of thecorresponding PGE type compounds encom- 20 passed by formulasXVllI-XXVII. For example, carbonyl reduction of 3-oxa PGE gives amixture of 3-oxa PGF and 3-oxa PGF These ring carbonyl reductions arecarried out by methods known in the art for ring carbonyl reductions ofknown prostanoic acid derivatives. See, for example, Bergstrom et al.,Arkiv Kemi 19, 563 (1963), Acta Chem. Scand. 16, 969 (1962), and BritishSpecification No. 1,097,533. Any reducing agent is used which does notreact with carbon-carbon double bonds or ester groups. Preferredreagents are lithium(tri-tertbutoxy)aluminum hydride, the metalborohydrides, especially sodium, potassium and zinc borohydrides, andmetal trialkoxy borohydrides, e.g., sodium trimethoxyborohydride. Themixtures of alpha and beta hydroxy reduction products are separatedinto.the individual alpha and beta isomers by methods known in the artfor the separation of analogous pairs of known isomeric prostanoic acidderivatives. See, for example, Bergstrom et al., cited above, Granstromet al., J. Biol. Chem. 240, 457 (1965), and Green et al., J. LipidResearch 5, 117 (1964). Expecially preferred as separation methods arepartition chromatographic procedures, both normal and reversed phase,preparative thin layer chromatography, countercurrent distributionprocedures, and column chromatography.

The various 3-oxa and 4-oxa PGA-type compounds encompassed by formulasXXXVIII-XLVII are prepared by acidic dehydration of the correspondingPGE type compounds encompassed by formulas XVIII-XX- VII. For example,acidic dehydration of 3-oxa PGE gives 3-oxa PGA These acidicdehydrations are carried out by methods known in the art for acidicdehydrations of known prostanoic acid derivatives. See, for example,Pike et al., Proc. Nobel Symposium II, Stockholm (1966), IntersciencePublishers, New York, pp. 162-163 (1967); and British Specification1,097,533. Alkanoic acids of 2 to 6 carbon atoms, inclusive, especiallyacetic acid, are-preferred acids for this acidic dehydration. Diluteaqueous solutions of mineral acids, e.g., hydrochloric acid, especiallyin the presence of a solubilizing diluent, e. g., tetrahydrofuran, arealso useful as reagents for this acidic dehydration, although thesereagents may cause partial hydrolysis of an ester reactant.

The various 3-oxa and 4-oxa PGB-type compounds encompassed by formulasXLVII-LVII are prepared by basic dehydration of the corresponding PGEtype compounds encompassed by formulas XVIII-xXVII, or by contacting thecorresponding PGA compounds encompassed by formulas XXXVIII-XLVII withbase. For example, both 3-oxa PGE and 3-oxa PGA give 3-oxa PGB ontreatment with base.

These basic dehydrations and double bond migrations are carried out bymethods known in the art for similar reactions of known prostanoic acidderivatives. See, for example, Bergstrom et al., J. Biol. Chem.2323,3555 (1963). The base is any whose aqueous solution has pH greaterthan 10. Preferred bases are the alkali metal hydroxides. A mixture ofwater and suffi- I The various transformations of 3-oxa and 4-oxa PGEtype compounds of formulas XVIII to XXV to the corresponding 3-oxaand4-oxa PGFq PGF PGA, and PGB type compounds are shown in Chart A,wherein Q, R R and are as defined above, and

wherein A is CH -CI-I or transCI-I=CH, Q is Chart A ,cH -v-cooa tLA -R26 "i: H Q

acl d O ,,cH -v-cR,- base ll carbonyl Q reduction ibase 2iH -V-COOR;"C'Rg at Q ,xzHa-v-cooa,

A-C'R u 2 H6 Q A R on CI-I -Cl-l The 3 -oxa and 4-oxa PGEg typecompounds of formulas XXVI and'XXVII are transformed to thecorresponding 3-oxa and 4-oxa PGF PGFgfl PGA and PGB compounds byanalogous reactions.

The various 3-oxa and 4-oxa dihydro-PGE dihydro- PGF dihydro-PGF Bdihydro-PGA,, and dihydro-PGB type compounds encompassed by formulasXXIV, XXV, XXXIV, XXXv, XLIV, XLV, LIV, and LV are prepared bycarbon-carbon double bond reduction of the corresponding PGE, PGF PGFPGA, and PGB type compound containing a trans double bond in thehydroxy-containing side chain. A cis or trans double bond or anacetylenic bond can also be present in the carboxy-terminated side chainof the unsaturated reactant, and will be reduced at the same time toCl-I Cl-I For example, dihydro-3-oxa- PGB is produced by reduction of3-oxa-PGE 3-oxa- PGE or 5,6-dehydro3-oxa-PGE These reductions arecarried out by reacting the unsaturated PGE, PGF PGF PGA, or PGB typecompound with diimide, following the general procedure described by vanTamelen et al., J. Am. Chem. Soc., 83, 3726 (1961). See also Fieser etal., Topics in Organic Chemistry, Reinhold Publishing Corp., New York,pp. 432-434 (1963) and references cited therein. The unsaturated acid orester reactant is mixed with a salt of azodiformic acid, preferably analkali metal salt such as the disodium or dipotassium salt, in

the presence of an inert diluent, preferably a lower alkanol such asmethanol or ethanol, and preferably in the absence of substantialamounts of water. At least one molecular equivalent of the azodiformicacid salt is used for each multiple bond equivalent of the unsaturatedreactant. The resulting suspension is then stirred, preferably withexclusion of oxygen, and the mixture is made acid, advantageously with acarboxylic acid such as acetic acid. When a reactant wherein R ishydrogen is used, that carboxylic acid reactant also serves to acidifyan equivalent amount of the azodiformic acid salt. A reactiontemperature in the range about 10 to about 40 C. is usually suitable.Within that temperature range, the reaction is usually complete withinless than 24 hours. The desired dihydro product is then isolated byconventional methods, for example, evaporation of the diluent, followedby separation from inorganic materials by solvent extraction.

In the case of the 3-oxa and 4-oxa unsaturated PGE, PGF and PGF typereactants, the reductions to the corresponding 3-oxa and 4-oxadihydr-PGE dihydro-PFG and dihydro-PGF compounds are also carried out bycatalytic hydrogenation. For that purpose, palladium catalysts,expecially on a carbon carrier, are preferred. It is also preferred thatthe hydrogenation be carried out in the presence of an inert liquiddiluent, for example, methanol, ethanol, dioxane, ethyl acetate, and thelike. Hydrogenation pressures ranging from about atmospheric to about 50p.s.i., and hydrogenation temperatures ranging from about 0 to about C.are preferred. The resulting dihydro product is isolated from thehydrogenation reaction mixture by conventional methods, for example,removal of the cat- CHART B cH, w cooR,

diimide or hydrogen catalyst diimide or hydrogen catalyst cH w cooa CHW-COOR diimide These diimide reductions and catalytic hydrogenations toproduce the same novel 3-oxa and 4-oxa dihydro compounds of thisinvention from the corresponding 3-oxa and 4-oxa PGE PGF PGF PGA and PGBtype compounds and also from the corresponding compounds with atrans-ethylenic or an acetylenic linkage in place of the cis-ethyleniclinkage in the carboxyl-terminated side chain, are shown in Chart C,wherein Q, R R and are as defined above, U is cis-CH=CH-, trans-CH=CH-,or C C-, and Y is -C H -OCR R or C l-l O-CR R CR R wherein p, q, R R Rand R are as defined above.

The 3-oxa and 4-oxa compounds of the PGE PGF PGF PGA and PGB typewherein the carbon-carbon double bond in the carboxy-terminated sidechain is in cis configuration are prepared by reduction of thecorresponding acetylenic 3-oxa and 4-oxa compounds, i.e., those with acarbon-carbon triple bond in place of said carbon-carbon double bond.For that purpose, there are used any of the known reducing agents whichreduce an acetylenic linkage to a cis-ethylenic linkage. Especiallypreferred for that purpose are diimide or hydrogen and a catalyst, forexample, palladium (5%) on barium sulfate, especially in the presence ofpyridine. See Fieser et al., Reagents for Organic Synthesis, pp.566-567, John Wiley & Sons,

Inc., New York, NY. (1967). These reductions are shown in Chart D,wherein Q, R R and are as defined above, and Y is C,,l-l ,,O-CR R or Cl-l -OCR R CR R 4-oxa cis compounds of the PGE PGF PGF PGA and PGB typeare also prepared as described hereinafter.

These 3-oxa and Y-COOR,

cH,-c E c Y cooR,

The 3-oxa and 4-oxa PGE type compounds of formulas XVIII to XXIII exceptwherein R is hydrogen, and the 3-oxa and 4-oxa PGA type compounds offormulas XXXVIII to XLIII except wherein R is hydrogen are prepared bythe series of reactions shown in Chart E, wherein Q, R and V are asdefined above, R and R are alkyl of one to 4 carbon atoms, inclusive, Ris the same as the above definition of R, except that R does not includehydrogen, R is alkyl of one to carbon atoms, inclusive, and indicatesexo or endo configuration with respect to the moiety attached to thecyclopropane ring.

The 3-oxa and 4-oxa PGE, type compounds of formulas XVIII and XIX, the3-oxa and 4-oxa 5,6-dehydro-PGE type compounds of formulas XXII andXXIII, the 3-oxa and 4-oxa PGA type compounds of formulas XXXVIII andXXXIX, and the 3-oxa and 4-oxa 5,6-dehydro-PGA type compounds offormulas XLII and XLIII are also prepared by the series of reactionsshown in Chart F, wherein Q, R R R and R are as defined above, Z is C,,H,,O-CR R C,,,I-I ,,,O-CR R CR R --C i C-C,,H- ,,OCR R or -C I CC,,I-IO-CR R -CR R and indicates exo or endo configuration with respect to themoiety attached to the cyclopropane ring.

It should be observed regarding the series of reactions shown in ChartsE and F, that the reaction starting with glycol LX in Chart E aresimilar to the reactions starting with glycol LXVII in Chart F. The onlydifferences here are the definitions of the divalent moieties V (ChartE) and Z (Chart F). V includes saturated, cis

and trans ethylenic, and acetylenic divalent moieties. Z is limited tothe saturated and acetylenic divalent moieties encompassed by V.

CHART E 10H OH R O SO ,CI-h-V-COOR CH-CH-R LVIII LIX LXII

LXllI LXIV CHART F LXV LXVI

CH I I CHCHR LXVII LXVIII H LXIX.

/ LXX CH-CI-L-R,

HO OSO R XLIII. On the other hand, final 3-oxa and 4-oxa PGE typecompounds of formula LXIX (Chart F) encompass only compounds of formulasXVIII, XIX, XXII, and XXIII, and final 3-oxa and 4-oxa PGA typecompounds of formula LXX (Chart F) encompass only compounds of formulasXXXVIII, XXXIX, XLII, and XLIII.

As will subsequently appear, an acetylenic intermediate of formula LIX,formula LX, or formula LXVII is transformed by reduction to thecorresponding cis or trans ethylenic intermediates of formulas LIX orLX, and an acetylenic intermediate of formulas LIX, LX, or LXVII, or acis or trans ethylenic intermediate of formulas LIX or LX is transformedby reduction to the corresponding saturated intermediate of formulasLIX, LX, or LXVII.

The initial bicyclo-ketone reactant of formula LXV in Chart F is alsoused as an initial reactant to produce the initial bicyclo-ketone cyclicketal reactant of formula LVIII in Chart E. The reactions of Chart Gwill produce cyclic ketal LVIII. Therein THP is tetrahydropyranyl, andd) is phenyl.

The bicyclo-ketone reactant of formula LXV exists in four isomericforms, exo and endo with respect to the attachment of the CI-I=CI-IRmoiety, and cis and trans with respect to the double bond in thatmoiety. Each of those isomers separately or various mixtures thereof areused as reactants according to this invention to produce substantiallythe same final 3-oxa or 4-oxa PBE or PGA type product mixture.

CHART G H LXXII LXXIII LVIII The process for preparing either the exo orendo configuration of the formula-LXV bicyclo-ketone is known to theart. See Belgian Patent No. 702,47 7', reprinted in Farmdoc CompleteSpecifications, Book 714, No. 30,905, page 313, Mar. 12, 1968. See WestGermany Offenlegungsschrift No. 1,937,912; reprinted in Farmdoc CompleteSpecifications, Book No. 14, No. 6869 R, Week R Mar. 18, 1970.

In said Belgian Patent No. 702,477, a reaction sequence capable offorming exo ketone LXV is as follows The hydroxy of 3-cyclopentenol isprotected, for example, with a tetrahydropyranyl group. Then adiazoacetic acid ester is added to the double bond to give an exo-endomixture of a bicyclo[3.l.0]hexane substituted at 3 with the protectedhydroxy and at 6 with a esterified carboxyl. The exo-endo mixture istreated with a base to isomerize the endo isomer in the mixture to moreof the exo isomer. Next, the carboxylate ester group at 6 is transformedto an aldehyde group, --CHO. Then, said aldehyde group is transformed bythe Wittig reaction, in this case to a moiety of the formulaCI-I=CI-I--R which is in exo configuration relative to the bicyclo ringstructure. Next, the protective group is removed to regenerate the 3-hydroxy which is then oxidized, for example, by the Jones reagent, i.e.,chromic acid (see J. Chem. Soc. 39 (1946)), to give said exo ketone LXV.

Separation of the cis-exo and trans-exo isomers of LXV is described insaid Belgian Patent No. 702,477. However, as mentioned above, thatseparation is usually not necessary since the cis-trans mixture isuseful as a reactant in the next process step.

The process described in said Belgian Patent No. 702,477 producing theexo form of bicyclo-ketone LXV uses, as an intermediate, the exo form ofa bicyclo [3.1.0]hexane substituted at 3 with a protected hydroxy, e.g.,tetrahydropyranyloxy, and at 6 with an esterified carboxyl. When thecorresponding endo compound is substituted for that exo intermediate,the process in said Offenlegungsschrift No. 1,937,912 leads to the endoform of bicyclo-ketone LXV. That endo compound to be used has theformula:

C lo

LXX l V COOCHa Compound LXXIV is prepared by reactingendo-bicyclo[3.l.0]-hexane-3-ol-6-carboxylic acid methyl ester which isthen reacted with dihydropyran in the presence of a catalytic amount ofPOCl to give the desired compound. This is then used as described insaid Offenlegungsschrift No. 1,93 7,912 to produce the endo form ofbicyclo-ketone LXV.

As for exo LXV, the above process produces a mixture of endo-cis andendo-trans compounds. These are separated as described for theseparation of exo-cis and exo-trans LXV, but this separation is usuallynot necessary since, as mentioned above, the cis-trans mixture is usefulas a reactant in the next process step.

In the process of said Belgian patent and said Offenlegungsschrift,certain organic halides, e.g., chlorides and bromides, are necessary toprepare the Wittig reagents used to generate the generic moiety,-CI'I=)\ 32 CHR of bicyclo-ketone LXV. These organic chlorides andbromides R CI-I Cl and R CH Br, are known in the art or can be preparedby methods known in the art.

To illustrate the availability of these .organic chlorides considerfirst the above-described 3-oxa and 4-oxa PGE-type compounds of formulasXVIII to XXVII wherein G is alkyl of one to 10 carbon atoms, inclusive,substituted with zero, one, 2, or 3 fluoro.

For those products wherein R is alkyl of one to 10 carbon atoms,substituted with Zero to 3 fluoro atoms, there are available themonohalo hydrocarbons, e.g., bromo-(or chloro-)rnethane, -ethane,-propane, -pentane, -octane, and -decane; and the monohalofluorohy- CH(CH CF (CH CH CL as described in Aliphatic Fluorine Compounds, A. M.Lovelace et al., Am. Chem. Soc. Monograph Series 1958, Reinhold Publ.Corp. Those halides not available are prepared by methods known in theart by reacting the corresponding primery alcohol R CI-I OI-I with PClPBr or any of the other halogen ating agents useful for this purpose.Available alcohols include CH CI-I(CF )CI-I OII, (Cl-I CI-ICI-I CH OH,(Cl-I CCI-I OI-I, CF CH(CI-I )Cl-I CH Ol-I, for example. For thosehalides of the formula R CI-I I-Ial wherein Hal is chloro or bromo R isR (CI-I (I being one, 2, 3, or 4, and R being isobutyl, tert-butyl,3,3-difluorobutyl, 4,4-difluorobutyl, or 4,4,4-trifluorobutyl, theintermediate alcohols are prepared as follows.

In the case of R being isobutyl or tert-butyl, known alcohols areconverted to bromides, thence to nitriles with sodium cyanide, thence tothe corresponding carboxylic acids by hydrolysis, and thence to thecorresponding primary alcohols by reduction, eg with lithium aluminumhydride, thus extending the carbon chain one carbon atom at a time untilall primary alcohols are prepared.

In the case of R being 3,3-difluorobutyl, the necessary alcohols areprepared from keto carboxylic acids of the formula, CH CO(CH -COOI-I,wherein r is 2, 3, 4, 5, or 6. All of those acids are known. The methylesters are prepared and reacted with sulfur tetrafluoride to produce thecorresponding CI-I=,CF- (CI-I ),-COOCH compounds, which are then reducedwith lithium aluminum hydride to CH CF- -(CH ),-CH OH. These alcoholsare then transformed to the bromide or chloride by reaction with FBI-301' PC13.

In the case of R being 4,4-difluorobutyl, the initial reactants are theknown dicarboxylic acids, HOO- C(CI-I ),COOH, wherein fis 3, 4, 5, 6, or7. These dicarboxylic acids are esterified to CH OOC(CH ),COOCH and thenhalf-saponified, for example with barium hydroxide, ),COOCH The freecarboxyl group is transformed first to the acid chloride with thionylchloride and then to an aldehyde by the Rosenmund reduction. Reaction ofthe aldehyde with sulfur tetrafluoride then gives CI-IF -(CI-I ),COOCHwhich by successive treatment with lithium aluminum hydride and PBr orPCI gives the necessary bromides or chlorides,

In the case of R being 4,4,4-trifluorobutyl, aldehydes of the formula CHOOC(CH ');--CHO are prepared as described above. Reduction of thealdehyde with sodium borohydride gives the alcohol CH OOC-(CH ),C1-lOl-l. Reaction with a hydrogen example for oexample hydrogen bromide,gives the corresponding halocarboxylic acid which by reaction withsulfur tetrafluoride gives the necessary CF --(CH )r-CH2BI' Or For theabove reactions of SE, see US. Pat. No. 3,211,723 and J. Org. Chem. 27,3164 (1962).

As mentioned above, formula XVIlI-to-LVII compounds with an alpha-fluorosubstitutent in a straight chain 3 to 7-carbon R i.e., R beingCl-lF(Cl-l -CH wherein g is one, 2, 3, 4, or 5, represent preferredembodiments among the novel 3-oxa and 4-oxa compounds of this invention.Among those, for example, is 3-oxal6-fiuoro-PGE The formula-LXVbicycloketones necessary to produce those monofluoro compounds areadvantageously prepared by reacting either of the above-mentionedbicyclo-aldehydes, exo

or endo, with a Wittig reagent prepared from CH --(CH ),,COCH Br andtriphenylphosphine. The aldehyde group is thereby transformed to Theresulting unsaturated ketone is reduced to the corresponding compound.Then -OH in that group is replaced with fluoro by known methods, forexample, directly by reand performic acid (formic acid plus hydrogenperoxide). Various isomeric glycols are obtained depending on suchfactors as whether olefin LXV is cis or trans and endo or exo, andwhether a cis or a trans hydroxylation reagent is used. These variousglycol mixtures can be separated into individual isomers by silica gelchromatography. However, this separation is usually not necessary, sinceall isomers of a particular glycol are equally useful as intermediatesaccording to this invention and the processes outlined in Chart E toproduce final products of formulas LXII and LXllI, and then, accordingto Chart A, B, C, and D to produce the other final products of thisinvention.

The transformation of glycol LXXllI to the cyclic ketal of formula LVIII(Chart E) is carried out by reacting said glycol with a dialkyl ketoneof the formula wherein R and R are alkyl of one to 4 carbon atoms,inclusive, in the presence of an acid catalyst, for example potassiumbisulfate or aqueous perchloric acid. A large excess of the ketone andthe absence of water is desirable for this reaction. Examples ofsuitable dialkyl ketones are acetone, methyl ethyl ketone, diethylketone, methyl propyl ketone, and the like. Acetone is preferred as areactant in this process.

Referring again to Chart E, cyclic ketal LVIII is transformed to cyclicketal LIX by alkylating with an alkylation agent of the formulal-lalCl-l- --VCOOR wherein R and V are as defined above, and Hal ischlorine, bromine, or iodine. Similarly, referring to Chart F, olefinLXV is transformed to olefin LXVI by alkylating with an alkylation agentof the formula HalCH ZCOOR wherein R Z, and Hal are as defined above.

Any of the alkylation procedures known in the art to be useful foralkylating cyclic ketones with alkyl halides and haloalkanoic esters areused for the transformations of LVIII to LIX and LXV to LXVI. See, forexample, the above-mentioned Belgian Pat. No. 702,477 for proceduresuseful here and used there to carry out similar alkylations, e.g.,employing the bicycle enamines.

For these alkylations, it is preferred that Hal be bromo or iodo. Any ofthe usual alkylation bases, e.g., alkali metal alkoxides, alkali metalamides, and alkali metal hydrides, are useful for this alkylation.Alkali metal alkoxides are preferred, especially tert-alkoxides. Sodiumand potassium are preferred alkali metals. Especially preferred ispotassium tert-butoxide. Preferred diluents for this alkylation aretertrahydrofuran and 1,2-dimethoxyethane. Otherwise procedures forproducing and isolating the desired formula LlX and LXVI compounds arewithin the skill of the art.

These alkylation procedures produce mixtures of alpha and betaalkylation products, i.e., a mixture of the formula-LIX products whereinthe CH- V-COOR moiety is attached in alpha configuration, withcorresponding compounds having that moiety attached in betaconfiguration, or a mixture of the formula-LXVI products withcorresponding compounds having the Cl-l Z-COOR moiety in the betaconfiguration. When about one equivalent of base per equivalent offormula LXV or LVIII ketone is used, the alpha configuration usuallypredominates. Use of an excess of base and longer reaction times usuallyresult in production of larger amounts of beta products. Thesealpha-beta isomer mixtures are separated at this stage or at anysubsequent stage in the multi-step processes shown in Charts E and F.Silica gel chromatography is preferred for this separation.

The necessary alkylating agents for the abovedescribed alkylations,i.e., compounds of the formulas HalCl-l V-COOR and Hal-CH -ZCOOR areprepared by methods known in the art.

There are eight groups of compounds encompassed by these two genera ofalkylating agents. Alkylating agents of the formula l-lal-CH Z-COOR,include compounds of the following formulas:

R5 R7 35 Hal-CH -C,,,H ,,,OCR LXXVI R Hal-CH,C E CC,,H ,,O-CCOOR, LXXVlll,

R R, HalCH -C E CC,,H 0C C -COOR,,, LXXVlll- Alkylating agents of theformula Hal-CH- -V-COOR, include the above-listed compounds of formulasLXXV, LXXVI, LXXVII, and LXXVIII, and also compounds of the followingformulas:

These alkylating agents of formulas LXXV to LXXXII are accessible tothose of ordinary skill in the art. For example, the 3-oxa alkylatingagents of formulas LXXV, LXXVII, LXXIX, and LXXX are advantageouslyprepared by reacting an alpha-hydroxy ester or acid of the formula HO-CRR COOR wherein R R and R are as defined above, with a compound of theformula, .ICH CnH ,,-G, JCH C- E CC l-l ,,-G, and JCH CH=CH-C H ,,G,respectively, wherein C,,H and C l-l are as defined above, .I is chloro,bromo, iodo, or a group transformable to one of those, for example,tetrahydropyranyloxy or mesyloxy, and G is chloro, bromo, iodo,mesyloxy, tosyloxy, or the like, in the presence of a strong base, forexample, sodium hydride when R is a carbon-containing group, and lithiumdiisopropyl amide when R is hydrogen. Alternatively, an alphabromo esteror acid of the formula BrCR R -COOR wherein R R and R are is definedabove, is reacted in the presence of a similar strong base with acompound of the formula JCH C l-I ,,OH, J CH C E CC,,H ,,OH, or JCl-I-CH=Cl-lC H ,,OH. When both R, and R in the ester are alkyl, it ispreferred to use the hydroxy acid or ester route. When there are twoalkyl groups in C I-[ or C,,H on the carbon to which -OH or G isattached, it is preferred to use the bromo acid or ester route. When aformula LXXV, LXXVII, LXXIX, or LXXX alkylating agent is desired whereinboth R and R are alkyl and C,,H or C H has two alkyl groups attached tothe carbon to which --O is attached, it is preferred that G be mesyloxyor tosyloxy, or that the Br of the bromo acid or ester be replaced withmesyloxy or tosyloxy, whereupon bases and reaction conditions known inthe art may be used, for example, potassium tert-butoxide in dimethylsulfoxide. Alternatively, this group of tetraalkyl compounds isadvantageously prepared by using the hydroxy acid or ester route with acompound wherein G is chloro, or by using the bromo acid or ester routewherein the bromo is replaced with chloro, using freshly precipitatedwet magnesium hydroxide in an inert solvent suspension as the base.Alternatively this group of tetraalkyl compounds is advantageouslyprepared by the hydroxy acid or ester route wherein G is iodo, andsilver oxide is used as the base. Any of these alternative routes is, ofcourse, useful to make the other compounds within the scope of formulasLXXV, LXXVII, LXXIX, and LXXX.

An alternative procedure generally applicable to the production of thealkylating agents of formulas LXXV, LXXVII, LXXIX, and LXXX comprisesreacting a compound of the formula J CH C,,H ,,Ol-I, JTCH C E CC,,H,,OH, or JCH2CH=)\ CHC,,H ,,OH with an ethylene oxide of the formulawherein R and R are as defined above, in the presence of an acidcatalyst, e.g., hydrochloric acid, sulfuric acid, or boron trifluoride.The alcohol which is usually the major product, i.e., JCH C,,H ,,OCR R-CH Ol-l, J-CH C E C-C,,H OCR R CH OH, or cis or trans JCH CH=CH-C,,H-,,-OCR R CH OH, is isolated, oxidized to the corresponding carboxylicacid with Jones reagent, and the acid esterified (R The 4-oxa alkylatingagents of formulas LXXVI, LXXVIII, LXXXI, and LXXXII are advantageouslyprepared as described above for the 3-oxa compounds, combining compoundsof the formula J -CH --C l-I- ,,,-G, J CH -C,,,H ,,,OH, JCH C E C-C l-l-G, J-CH C E C--C,,H ,,qOH, JCH. CH=CHC l-l G, and J-CH CH=CHC l-l- ,,OH,with B-hydroxy acids or esters and B-halo acids or esters of theformulas HOCR R CR R COOR and Br-CR R -CR R COOR or trimethylene oxidesof the formula All of the procedures, preferences, and alternativesdescribed above for the preparation of the 3-oxa alkylating agents areapplicable to the preparation of these 4-oxa alkylating agents.

The alkylating agents of formulas LXXV to LXXXII are esters. When analpha or beta hydroxy acid or bromo acid is used as a reactant asdescribed above, the resulting product is a carboxylic acid. This acidis esterified to the corresponding formulas LXXV-to-LXXXII alkylatingagent by known procedures. As will be described hereinafter, the estermoiety R is chosen according to the desired type of final 3-oxa or 4-oxaprostaglandin-like product.

The alpha-hydroxy, alpha-halo, beta-hydroxy, and betahalo acids andesters and the ethylene and triwherein THP represents2-tetrahydropyranyl, and each free valenceis attached to hydrogen or toalkyl, with a total of zero to 9 attached alkyl carbon atoms. Saidcompounds are within the scope of J -CH C,,H- ,,OH as above defined, andare advantageously prepared by hydroxylating by known methods, olefinsof the formula to give the glycols which are transformed by knownmethods to the above tetrahydropyranyl ethers. These ethers are alsotransformed by known methods to compounds within the scope of J-CH C,,H,,G as above defined.

Consider the compounds wherein THP is as above defined, and the freevalences are attached to hydrogen or to alkyl, with a total of zero to 8attached alkyl carbon atoms. Said compounds are within the scope of JCHC,,H ,,-OH as above. defined, and are advantageously prepared by knownmethods from beta-hydroxyesters of the formula are available wherein Ris methyl or ethyl and the free valences are attached to hydrogen or toalkyl. Said esters areavailable through methods known in the art, e.g.,the Reformatsky reaction. Said compounds are also transformed by knownmethods to compounds within the scope of JCH -C,,H ,,G as above defined.

Consider the compounds wherein THP is as defined above and the freevalences are attached to hydrogen or to alkyl, with a total of zero to 7attached alkyl carbon atoms. Said compounds are within the scope of JCHC,,H ,,OH as above defined, and are advantageously prepared by knownmethods from the known succinic acid half esters of the formula whereinR is methyl or ethyl, the carboxyl end being transformed to THP-OCH andthen the -COOR end being transformed to both by known methods. Saidcompounds are also transformed by known methods to compounds within thescope of J'-CH C,,H ,,G as above defined.

Consider the compounds IIII wherein THP is as defined above and the freevalences are attached to hydrogen or to alkyl, with a total of zero to 6attached alkyl carbon atoms. Said compounds are within the scope ofJ-Cl-l C,,l-l ,,-Ol-l as above defined, and are advantageously preparedby known methods from wherein THP and the free valence attachments areas above defined, and R is methyl or ethyl. These ester reactants areprepared by' known methods from reactants whose preparation is describedin the preceeding paragraph. Said compounds are also transformed byknown methods to

1. AN OPTICALLY ACTIVE COMPOUND OF THE FORMULA:
 2. A racemic compoundaccording to claim
 1. 3. An optically active compound according toclaim
 1. 4. A compound according to claim 3 wherein CnH2n is straightchain alkylene of one to 5 carbon atoms, inclusive.
 5. A compoundaccording to claim 4 wherein CnH2n is trimethylene.
 6. A compoundaccording to claim 5 wherein R5 and R6 are hydrogen or methyl, being thesame or different.
 7. A compound according to claim 6 wherein R5 and R6are hydrogen.
 8. A compound according to claim 7 wherein R2 is pentyl.9. A compound according to claim 8 wherein Q is
 10. A compound accordingto claim 8 wherein Q is
 11. A compound according to claim 10 wherein R1is hydrogen or alkyl of one to 4 carbon atoms, inclusive, including thepharmacologically acceptable salts thereof when R1 is hydrogen.
 12. Acompound according to claim 11 wherein R1 is hydrogen or alkyl of one to4 carbon atoms, inclusive.
 13. A compound according to claim 12 whereinR1 is hydrogen, methyl, or ethyl.
 14. 3-Oxa-PGF1 , a compound accordingto claim
 13. 15. 3-Oxa-PGF1 , methyl ester, a compound according toclaim
 13. 16. 15 -Methyl-3-oxa-PGF1 , a compound according to claim 13.17. 15-Methyl-3-oxa-PGF1 , methyl ester, a compound according to claim13.
 18. An optically active compound of the formula:
 19. A racemiccompound according to claim
 18. 20. An optically active compoundaccording to claim
 18. 21. A compound according to claim 20 whereinCnH2n is straight chain alkylene of one to 5 carbon atoms, inclusive.22. A compound according to claim 21 wherein CnH2n is trimethylene. 23.A compound according to claim 22 wherein R5 and R6 are hydrogen ormethyl, being the same or different.
 24. A compound according to claim23 wherein R5 and R6 are hydrogen.
 25. A compound according to claim 24wherein R2 is pentyl.
 26. A compound according to claim 25 wherein Q is27. A compound according to claim 25 wherein Q is
 28. A compoundaccording to claim 27 wherein R1 is hydrogen or alkyl of one to 4 carbonatoms, inclusive, including the pharmacologically acceptable saltsthereof when R1 is hydrogen.
 29. A compound according to claim 28wherein R1 is hydrogen or alkyl of one to 4 carbon atoms, inclusive. 30.A compound according to claim 29 wherein R1 is hydrogen, methyl, orethyl.
 31. A compound according to claim 30 wherein the C-5 to C-6double bond in the carboxyl-terminated side chain is in the cisconfiguration.
 32. 3-Oxa-PGF2 , a compound according to claim
 31. 33.3-Oxa-PGF2 , methyl ester, a compound according to claim
 31. 34.15-Methyl-3-oxa-PGF2 , a compound according to claim
 31. 35.15-Methyl-3-oxa-PGF2 , methyl ester, a compound according to claim 31.36. An optically active compound of the formula:
 37. A racemic compoundaccording to claim
 36. 38. An optically active compound according toclaim
 36. 39. A compound according to claim 38 wherein CnH2n is straightchain alkylene of one to 5 carbon atoms, inclusive.
 40. A compoundaccording to claim 39 wherein CnH2n is trimethylene.
 41. A compoundaccording to claim 40 wherein R5 and R6 are hydrogen or methyl, beingthe same or different.
 42. A compound according to claim 41 wherein R5and R6 are hydrogen.
 43. A compound according to claim 42 wherein R2 ispentyl.
 44. A compound according to claim 43 wherein Q is
 45. A compoundaccording to claim 43 wherein Q is
 46. A compound according to claim 45wherein R1 is hydrogen or alkyl of one to 4 carbon atoms, inclusive,including the pharmacologically acceptable salts thereof when R1 ishydrogen.
 47. A compound according to claim 46 wherein R1 is hydrogen oralkyl of one to 4 carbon atoms, inclusive.
 48. A compound according toclaim 47 wherein R1 is hydrogen, methyl, or ethyl. 49.3-Oxa-5,6-didehydro-PGF1 , a compound according to claim
 48. 50.3-Oxa-5,6-didehydro-PGF1 , methyl ester, a compound according to claim48.
 51. 15-Methyl-3-oxa-5,6-didehydro-PGF1 , a compound according toclaim
 48. 52. 15-Methyl-3-oxa-5,6-didehydro-PGFPGF1 , methyl ester, acompound according to claim
 48. 53. An optically active compound of theformula:
 54. A racemic compound according to claim
 53. 55. An opticallyactive compound according to claim
 53. 56. A compound according to claim55 wherein CnH2n is straight chain alkylene of one to 5 CARBON atoms,inclusive.
 57. A compound according to claim 56 wherein CpH2p istrimethylene.
 58. A compound according to claim 57 wherein R5 and R6 arehydrogen or methyl, being the same or different.
 59. A compoundaccording to claim 58 wherein R5 and R6 are hydrogen.
 60. A compoundaccording to claim 59 wherein R2 is pentyl.
 61. A compound according toclaim 60 wherein Q is
 62. A compound according to claim 60 wherein Q is63. A compound according to claim 62 wherein R1 is hydrogen or alkyl ofone to 4 carbon atoms, inclusive, including the pharmacologicallyacceptable salts thereof when R1 is hydrogen.
 64. A compound accordingto claim 63 wherein R1 is hydrogen or alkyl of one to 4 carbon atoms,inclusive.
 65. A compound according to claim 64 wherein R1 is hydrogen,methyl, or ethyl.
 66. 3-Oxa-13,14-dihydro-PGF1 , a compound according toclaim
 65. 67. 3-Oxa-13,14-dihydro-PGF1 , methyl ester, a compoundaccording to claim
 65. 68. 15-Methyl-3-oxa-13,14-dihydro-PGF1 , acompound according to claim
 65. 69. 15-Methyl-3-oxa-13,14-dihydro-PGF1 ,methyl ester, a compound according to claim
 65. 70. An optically activecompound of the formula: